Activation of protein kinase C-ζ and phosphatidylinositol 3'-kinase and promotion of macrophage differentiation by insulin-like growth factor-I

Qiang Liu, Wei Ning, Robert Dantzer, Gregory G. Freund, Keith W. Kelley

    Research output: Contribution to journalArticlepeer-review

    Abstract

    Phosphoinositides that are phosphorylated at the D3 position have been reported to activate an atypical, Ca2-independent protein kinase C (PKC) isoform designated PKC-ζ, and overexpression of this enzyme leads to monocytic differentiation. In this study, we cultured human HL-60 promyeloid cells with vitamin D3 and insulin-like growth factor-I (IGF-I), a 70-amino- acid peptide that activates phosphatidylinositol 3'-kinase (PI 3-kinase) in murine promyeloid cells. Two days later, the proportion of cells differentiating into macrophages in serum-free medium, as assessed by expression of the α-subunit of the β2 integrin CD11b, increased from 5 ± 1% to 25 ± 3%. Addition of IGF-I increased the proportion of cells differentiating into CD11b-positive macrophages to 78 ± 5 %. In the absence of vitamin D3, IGF-I did not induce expression of CD11b (6 ± 1%). The IGF- I-promoted macrophage differentiation was blocked specifically by preincubation of HL-60 cells with a mAb (αIR3) directed against the IGF type I receptor. Similarly, pretreatment of cells with either αIR3 or an IGF- binding protein, IGFBP-3, led to a 75% inhibition of CD11b expression when cells were cultured with vitamin D3 in serum-containing medium. IGF-I, but not vitamin D3, caused a sevenfold increase in the enzymatic activity of both PI 3-kinase and atypical PKC-ζ. Inhibition of IGF-I-inducible PI 3- kinase with either wortmannin or LY294002 abrogated the IGF-I-induced activation of PKC-ζ and totally blocked the enhancement in macrophage differentiation caused by IGF-I. These data establish that PKC-ζ is a putative downstream target of PI 3-kinase that is activated during IGF-I- promoted macrophage differentiation.

    Original languageEnglish (US)
    Pages (from-to)1393-1401
    Number of pages9
    JournalJournal of Immunology
    Volume160
    Issue number3
    StatePublished - Feb 1 1998

    ASJC Scopus subject areas

    • Immunology and Allergy
    • Immunology

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